Accumulation of Long-Chain Glycosphingolipids during Aging Is Prevented by Caloric Restriction

Chronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence.We hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo), middle aged (9 mo) and old (17 mo) C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer) and lactosylceramides (LacCer), with C14- and C16-lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals.This study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular processes fundamental to mammalian aging

Does the use of health technology assessment have an impact on the utilisation of health care resources? Evidence from two European countries

Objectives: A centralised approach to health technology assessment (HTA) may facilitate optimal use of HTA resources. A regional approach may increase the chances of local implementation of recommendations. This study aimed to compare assessment procedures in England (centralised HTA approach) with Spain (regional HTA approach) discussing key challenges and opportunities from both approaches. Methods: We compared technology assessments of anticancer medicines in the two jurisdictions from 2008 to 2015. In order to assess the implementation of HTA recommendations, we assessed trends in medicine usage using regression methods. We used IQVIA data, from 2011 to 2016, for a sample of 11 medicines. We used CatSalut data from Catalonia to assess the implementation of local recommendations. Results: In England 66 assessments were undertaken by the National Institute for Health and Care Excellence (NICE), using a standardised methodology. In Spain there were 79 reports undertaken by a range of bodies using a shared process and coordinated through the GENESIS collaboration; the assessment methods used varied substantially. Overall, the recommendations in the two jurisdictions were similar. Regression analyses indicate that where there is a positive recommendation by HTA bodies, the usage of the medicine responds most strongly (p<0.001) in Catalonia (=4.892), followed by England ( =3.120) and Spain ( =1.693). Conclusions: This study suggests that medicine utilisation does respond to the positive recommendations of HTA bodies. However, if HTA capacity is organised primarily regionally, considerable effort may be required in coordination, in order to ensure consistent and rigorous assessments and adequate implementation of HTA findings

Costs and Consequences of the Family Nurse Partnership (FNP) Programme in England: Evidence from the Building Blocks Trial

Background: The Family Nurse Partnership (FNP) is a licensed intensive home visiting intervention programme delivered to teenage mothers which was originally introduced in England in 2006 by the Department of Health and is now provided through local commissioning of public health services and supported by a national unit led by a consortium of partners. The Building Blocks (BB) trial aimed to explore the effectiveness and cost-effectiveness of this programme. This paper reports the results of an economic evaluation of the Building Blocks randomised controlled trial (RCT) based on a cost-consequence approach. Methods: A large sample of 1618 families was followed-up at various intervals during pregnancy and for two years after birth. A cost-consequence approach was taken to appraise the full range of costs arising from the intervention including both health and social measures of cost alongside the consequences of the trial, specifically, the primary outcomes. Results: A large number of potential factors were identified that are likely to attract additional costs beyond the implementation costs of the intervention including both health and non-health outcomes. Conclusion: Given the extensive costs and only small beneficial consequences observed within the two year follow-up period, the cost-consequence model suggests that the FNP intervention is unlikely to be worth the substantial costs and policy makers may wish to consider other options for investment. Trial registration: ISRCTN23019866 (20/04/2009) Keywords Randomised controlled trial, Cost-consequence analysis, Pregnancy in adolescence, Prenatal care, Maternal health, Home visitin

Five-year follow-up results of the PROFHER trial comparing operative and non-operative treatment of adults with a displaced fracture of the proximal humerus

AIMS: The PROximal Fracture of the Humerus Evaluation by Randomisation (PROFHER) randomised clinical trial compared the operative and non-operative treatment of adults with a displaced fracture of the proximal humerus involving the surgical neck. The aim of this study was to determine the long-term treatment effects beyond the two-year follow-up. PATIENTS AND METHODS: Of the original 250 trial participants, 176 consented to extended follow-up and were sent postal questionnaires at three, four and five years after recruitment to the trial. The Oxford Shoulder Score (OSS; the primary outcome), EuroQol 5D-3L (EQ-5D-3L), and any recent shoulder operations and fracture data were collected. Statistical and economic analyses, consistent with those of the main trial were applied. RESULTS: OSS data were available for 164, 155 and 149 participants at three, four and five years, respectively. There were no statistically or clinically significant differences between operative and non-operative treatment at each follow-up point. No participant had secondary shoulder surgery for a new complication. Analyses of EQ-5D-3L data showed no significant between-group differences in quality of life over time. CONCLUSION: These results confirm that the main findings of the PROFHER trial over two years are unchanged at five years. Cite this article: Bone Joint J 2017;99-B:383-92

A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function

$\textbf{PURPOSE}$ Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function. $\textbf{METHODS}$ Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m$^{2}$), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m$^{2}$) and C (severe impairment: CrCL <30 mL/min/1.73 m(2)) received cabazitaxel 25 mg/m$^{2}$ (A, B) or 20 mg/m(2) (C, could be escalated to 25 mg/m$^{2}$), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F$_{U}$) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m$^{2}$) versus a control (90 mL/min/1.73 m$^{2}$). $\textbf{RESULTS}$ Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1-20]; Cohort A: 5 [2-13]; Cohort B: 3 [1-15]; and Cohort C: 5 [1-20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80-1.13) and 0.89 (0.61-1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88-1.27) and 1.14 (0.76-1.71); and F U 0.99 (0.94-1.04) and 0.97 (0.87-1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (-0.15 to 0.28); AUC/dose -0.07 (-0.30 to 0.16); and F U 0.02 (-0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports. $\textbf{CONCLUSIONS}$ Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.This study was supported by Sanofi. Javier Garcia-Corbacho acknowledges clinical fellowship support from SEOM. Experimental Cancer Medicine Centre (ECMC) and NIHR Biomedical Research Centre (BRC) funding is also acknowledged for the Cambridge Cancer Centre